Buffered para-aminosalicylic acid oral compositions



United States Pat fif '0 BUFFERED PARA-AMINOSALICYLIC ACID ORALCOMPOSITIONS Milton Feier, New York, and Myron Pantzer, Brooklyn, N.Y.,assignors to The Panray Corp., Englewood, NJ., a corporation of New YorkNo Drawing. Filed Mar. 10, 1954, Ser. No. 415,417 4 Claims. (Cl. 167-65)This invention is that of pharmaceutical preparations containingpara-aminosalicylic' acid (briefly designated PAS) accompanied withcertain agents that enable the administration of PAS in the treatment oftuberculosis, with practical elimination of the undesirable eflectsnormally experienced by patients taking PAS or its available salts.

More specifically the preparations of the invention contain the PAStogether with certain proportions of calcium carbonate and dihydroxyaluminum aminoacetate. These.

enable the administration of an effective dosage of the PAS whereby thePAS is buffered on dissolving in the alimentary tract, and at the sametime in a size of, tablet that can be comfortably taken by the patient.

PAS continues to be a very valuable drug in the treatment oftuberculosis. Tubercular patients require ten to twelve grams of itdaily for periods from six months to a year, and generally take six halfgram tablets four times a day. Its administration and at such a regimenfrequently causes gastro-intestinal symptoms. Because of advantages insolubility, sodium para-aminosalicylate became a very popular salt formfor providing this medication. Twenty-eight to thirty-four tablets ofthe sodium salt provide the daily requirement of active PAS.

The sodium salt likewise causes frequent severe gastrointestinalirritations. These abdominal distresses include nausea, vomiting,diarrhea, colicky abdominal pain, and other upsets. Such irritatingeffects are highly variable within each batch of sodiumpara-aminosalicylate and also differ between batches. Many patientscannot tolerate this drug in adequate doses or in the prolonged regimenrequired.

Many patients then do not take the required number of tablets of PAS orits sodium salt and often toss them away if not watched. Some patientscannot tolerate any form of PAS. In many cases, these disturbancesnecessitated discontinuing for a few'days administration of sodiumpara-aminosalicylate (briefly called sodium-PAS) and then resuming it.Enteric coating the sodium-PAS tablets, in an attempt to avoid theseundesirable effects, does not result in satisfactorily doing so.

In many instances, these gastro-intestinal disturbances are amelioratedby administering aluminum hydroxide gel as an antacid. However, thatintroduces a different disadvantage for the aluminum hydroxideapparently inhibits not alone the absorption of the sodium-PAS or thePAS but possibly also its retention in the blood stream. This isindicated by the following results obtained in a study: sodium-PASshowed a blood level of four milligrams percent after two hours, and ofbetween eighttenths and one milligram percent after four hours. However,with the additional administration of aluminum hydroxide gel, it showeda blood level of one milligram percent after two hours and no trace atall at four hours.

Calcium para-aminosalicylate (briefly called calcium- PAS) is morepalatable than sodium-PAS and appears to provoke less gastro-intestinalside effects than it. However, some patients find it more irritating andwith them "ice and others it is not well tolerated. Moreover, thetherapy with calcium-PAS is considerably more costly. This is so becausecalcium-PAS for tablet making purposes costs about one andthree-quarters times what PAS for tablet making use costs.

It might be attempted to replacecalcium-PAS by PAS together withthe'necessary equivalent amount of calcium carbonate to seek to obtainthe same improved results at lower cost. However, the quantity of thelatter required is sogreat that the resulting tablet is of a size thatwould be very diflicult to swallow even as a single tablet 'let alone atleast six at a time and four times daily.

The compositions of this invention not only overcome thisdiflicult-to-swallow tablet size disadvantage, but also lack for atleast the vast majority of patients the various gastro-intestinaldisturbances provoked by PAS alone and its salts. Moreover, thecompositions of the invention require no enteric coating.

This is accomplished by using calcium carbonate with PAS and reducingthe quantity of the former considerably below the molecular orstoichiometric equivalent amount required by the quantity of PAS used,and replacing some of the omitted calcium carbonate by dihydroxyaluminum arninoacetate (briefly termed DAA) likewise in a quantitysignificantly below its PAS molecular equivalent, so that the calciumcarbonate and the DAA jointly are below the total stoichiometricequivalent amount required by the PAS present.

Thus, broadly considered, the compositions of the invention comprise PASas the tuberculostatic constituent accompanied by from about one toabout two parts of DAA and from about four to about three parts ofcalcium carbonate for about twenty parts of PAS. Considered otherwise,each tablet containing one-half gram of PAS.

contains also from about twenty-five to about fifty milligrams of "DAAand also from about one hundred to seventy five milligrams of calciumcarbonate. words, within the just indicated ranges, the higher thecontent of DAA the lower that of the calcium carbonate, and vice versa.

In still another way, the compositions of the invention contain PASaccompanied by from about three-quarters to about four-fifths of itsstoichiometric equivalent of DAA and calcium carbonate jointly and withthe DAA in.

the proportions of from about one-quarter to about twothirds of thecalcium carbonate.

The PAS with the DAA and calcium carbonate in the foregoing proportionsto one another can be worked up with suitable compatible diluents andbinders and made up into tablets containing, for example, one-half gramof PAS each. These tablets require no enteric coating and even no sugarcoating. While tablets are the most advantageous dosage form, thesecompositions of the invention can also be put up in capsules or aspharmaceutical powders. In the capsule and powder dosage forms, it i maybe possible to forego admixing any diluent ingredients.

Conveniently suitable tablets are prepared by using the three essentialingredients in such proportions to provide per tablet one-half gram ofPAS, seventy-five milligrams of calcium carbonate and fifty milligramsof DAA. Known, suitable and compatible diluents and binders can beincluded, and the tablets prepared in the usual manner. The resultingtablets, containing the indicated respective r amounts of the threeessential ingredients, provide about a thirty percent reduction in thenumber of tablets. the patient needs to take daily. This is so becausetwenty four of these tablets daily provide the para-aminosalicylic acidequivalent of the thirty-four tablets of sodium-PAS required to be takendaily.

0n oral administration in any of their applicable dosage forms, thecompositions of the invention are efiective In other processes; and are.unusually well% tolerated. They: are.

notably better toleratedthan a composition of PAS, magnesiumcarbonateand aluminum glycinate also developed in the project that yielded thecompositions of this invention. The compositions claimed herein do notprovoke the gastro-intestinal. disturbances experienced with the earlierpreparations containing PAS or its salts, to overcome which the patientstook sodium bicarbonate.

There areindications that the compositions of this invention tend toprovide a somewhat lower rate of elimination of the drug fromthebloodstream than occurs-from the same amount of PASalone or as sodium-PAS orcalcium-PAS, therebyproviding a longer sustained blood level ofYPAS..

In the compositions of. the. invention, containing the three essentialingredients, calcium carbonate, DAA, and PAS, the latter is thusbuffered without introducing the sodium ion. Thus, these compositionscan be used by patients required to follow a restricted-sodium intake.

While the invention has been explained in detail in relation to variousspecific embodiments of it, it is understood that many modifications andsubstitutions can be made in it within the scope of the appended claimswhich are intended also to cover equivalents of these specificembodiments.

What is claimed is:

1. A pharmaceutical preparation for oral administration and effective inthe treatment of tuberculosis, which comprises from about one to abouttwo parts of dihydroxy aluminum amino acetate and from about four toabout three parts of calcium carbonate to about twenty parts ofpara-aminosalicylic acid, which preparation is generally free of thegastric disturbances ordinarily provoked by para-aminosalicylic acid andits water-soluble salts when taken alone.

2. A pharmaceutical preparation for oral administration and effective inthe treatment of tuberculosis, which comprises para-aminosalicylic acid(PAS) together with calcium. carbonate and dihydroxy aluminumaminoacetate with the latter in the proportions of from about onequarterto about two-thirds of the calcium carbonate, and the calcium carbonateand dihydroxy aluminum aminoacetate constituting together from aboutseventy-five to about eighty percent of their total stoichiometricequivalent of the PAS, which preparation is generally free of thegastric disturbances ordinarily provoked" by paraaminosalicylic acid andits water-soluble salts when taken alone.

3 A pharmaceutical preparationvin solid'dosage units for oraladministration and effective in the treatment of tuberculosis, whichcomprises per dosage unite about onehalf gram of para-aminosalicylicacid, about seventy'five milligrams of calcium carbonateand about fiftymilligrams of dihydroxy aluminum aminoacetate, which preparation isgenerally free of the gastric disturbances ordinarily provoked bypara-aminosalicylic.acid and its water-soluble salts when taken alone.

4. A pharmaceutical preparation in tablet form and efiective in thetreatment of tuberculosis, which comprises per tablet about one-halfgram of para-aminosalicylic acid, about seventy-five milligrams ofcalcium carbonate and about fifty milligrams of dihydroxy aluminumaminoacetate, which preparation is generally free of the gastricdisturbances ordinarily provoked by para-aminosalicylic acid and itswater-soluble salts when taken alone.

References Cited in the file of this patent UNITED STATES PATENTSAbramson Oct. 28, 1947 Smith June 21, 1955 OTHER REFERENCES

1. A PHARMACEUTICAL PREPARATION FOR ORAL ADMINISTRATION AND EFFECTIVE INTHE TREATMENT OF TUBERCULOSIS, WHICH COMPRISES FROM ABOUT ONE TO ABOUTTWO PARTS OF DIHYDROXY ALUMINUM AMINOACETATE AND FROM ABOUT FOUR TOABOUT THREE PARTS OF CALCIUM CARBONATE TO ABOUT TWENTY PARTS OFPARA-AMINOSALICYLIC ACID, WHICH PREPARATION IS GENERALLY FREE OF THEGASTRIC DISTURBANCES ORDINARILY PROVOKED BY PARA-AMINOSALICYLIC ACID ANDITS WATER-SOLUBLE SALTS WHEN TAKEN ALONE.